The aims of this experimental marrow stem cell transplantation (SCT) program is 1) to improve the outcome after allogeneic SCT by optimizing the stem cell and lymphocyte doses of the transplant, and 2) to exploit the antitumor effect of donor immune cells to treat hematological and other malignant diseases by adoptive immunotherapy. Results of over 78 bone marrow stem cell transplants recently analyzed indicate that a high stem cell dose (greater than 3 million CD34+ stem cells/kg recipient weight) results in a low transplant-related mortality and a reduced relapse rate in patients both at low and high risk of relapse. The use of peripheral blood stem cell collection (instead of marrow collections) in the last 32 patients has improved outcome because the stem cell doses mostly exceeded 3 million/kg. Improved graft manipulation has also made it possible to reduce the lymphocyte dose in most transplants to a level which does not cause graft-versus-host disease (GVHD). The first step in controlling immune recovery after allogeneic transplantation has therefore been achieved. The continuing challenge is to add-back lymphocytes to reconstruct the recipient's immune system without causing GVHD. This is currently partially achieved with a delayed add-back of donor T cells (only 2/25 evaluable recipients developed GVHD after T cell add-back and the incidence of chronic GVHD is low 4/20 evaluable patients). Ongoing research focuses on a "selective depletion" of alloreacting donor cells to allow the add-back of large numbers of immune competent lymphocytes while not causing GVHD. Four new transplant protocols have been started 1) Non-myeloablative (low intensity) stem cell transplants for patients normally considered too old to withstand a conventional bone marrow transplant (7 patients); 2) non-myeloablative transplants to confer a graft-versus-tumor effect in metastatic renal cell carcinoma (2 patients); 3) non-myeloablative transplants to confer a graft-versus-tumor effect in metastatic melanoma (4 patients); and 4) transplants from partially matched family donors in patients with high risk hematologic malignancies (3 patients). Preliminary results with non-myeloablative transplants suggest that the procedure is associated with low transplant-related mortality. The complete and stable resolution of pulmonary metastases in a patient with renal cell carcinoma and the absence of any detectable minimal residual disease in a patient with chronic myeloid leukemia is proof of principle that the transplant approach can exert a graft-versus-tumor effect. The partially matched transplant procedure has allowed engraftment. Further evaluation will be possible with larger numbers of recipients and longer follow up. Laboratory research focuses on four objectives: 1) the detection and expansion of graft versus-leukemia/tumor lymphocytes to understand interactions between alloreacting T cells and malignant cells; 2) the discovery of new antigens present in leukemia cells capable of initiating a graft-versus-leukemia (GVL) response in allogeneic T cells; 3) development of techniques to select and expand leukemia and tumor reacting T cells for adoptive immunotherapy; and 4) development of detection assays for antigen specific T cells for the direct monitoring of in vivo specific T cell responses to leukemia, tumor and viral antigens and to monitor the impact of immunotherapeutic maneuver. As an adjunct to the study of interactions between T cells and marrow cells two clinical protocols study the use of immunosuppressive therapy to improve hematological function in diseases believed to represent immune-mediated marrow suppression. A protocol evaluating antithymocyte globulin (ATG) treatment in myelodysplastic syndrome has been completed showing a 42% responses rate with transfusion independence in 60 patients. A new study comparing ATG with cyclosporine is now started. There is a continuing protocol studying cyclosporine as treatment for large granular lymphocytic (LGL) leukemia. Fourteen patients have been treated. Response rates are in the region of 60%. Laboratory studies show that ATG treatment prevents a direct inhibitory effect of T cells on marrow progenitors. Cyclosporine appears to produce similar effects in patients with LGL leukemia.